Fibroblast-like synoviocytes (FLS) in the intimal lining of the joint synovium control the composition of the synovial fluid and extracellular matrix (ECM) of the joint lining. In rheumatoid arthritis (RA), FLS become aggressive and invasive, contributing to many aspects of RA pathology. FLS produce matrix metalloproteinases (MMPs) that break down the ECM, directly invade and digest the articular cartilage, promote bone erosion, and promote inflammation through secretion of interleukin 6 (IL-6), chemokines, and other inflammatory mediators (1-6). FLS are highly sensitive to the inflammatory environment present in rheumatoid joints. Growth factors, especially platelet-derived growth factor (PDGF), stimulate FLS invasiveness. Inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1), enhance FLS aggressiveness, pro-inflammatory features and MMP production (5, 6). Targeting of molecules that control FLS invasiveness and inflammatory output is being considered an option for development of new therapies for RA (7-9).
Many signaling pathways controlling FLS behavior rely upon phosphorylation of proteins on tyrosine residues (8), which results from the balanced action of protein tyrosine kinases (PTKs) and phosphatases (PTPs). Applicants recently profiled the expression of PTPs in FLS from RA patients (RA FLS), and showed that PTPN11, encoding the SH2-domain containing PTP 2 (SHP-2), is overexpressed in RA FLS compared to FLS from osteoarthritis (OA) patients (10). Functional studies revealed that SHP-2 mediates the aggressive phenotype of RA FLS by promoting activation of focal adhesion kinase (FAK), leading to enhanced survival, invasiveness, and responsiveness to PDGF and TNF stimulation (10). FAK is a ubiquitously expressed non-receptor tyrosine kinase that acts as a critical mediator of cell motility and invasiveness (11) and promotes cell resistance to apoptosis (12). FAK activation is dependent upon phosphorylation on Tyr397 induced by integrin-mediated cell adhesion (11,12). This site can be autophosphorylated by FAK or phosphorylated by SRC family kinases (SFKs). Phospho-Tyr397 provides a docking site for SFKs, which phosphorylate other tyrosine residues of FAK, resulting in FAK activation. FAK may act as an important mediator of the anomalous behavior of RA FLS. Increased levels of phospho-FAK were shown in lining cells from RA synovial tissue compared to normal tissue (13). Importantly a recent epigenomics study showed that the FAK pathway is a hotspot of epigenetic anomalies in RA FLS (14).
RPTPα, encoded by the PTPRA gene, is a ubiquitously expressed PTP (17, 18). RPTPα is a critical positive regulator of signaling through dephosphorylation of the SFK C-terminal inhibitory tyrosine residue (Tyr527 in SRC) (16, 18-20). Dephosphorylation of SRC-Tyr527 enhances SRC activation, leading to tyrosine phosphorylation of FAK and other substrates. Fibroblasts from PTPRA KO mice showed increased phosphorylation of SRC- Tyr527, reduced SFK tyrosine kinase activity, reduced phosphorylation of FAK-Tyr397, and reduced SRC/FAK association (15, 20).
There are provided herein, inter alia, methods and compositions for treatment of autoimmune diseases including invasiveness of FLS in RA.